Revealing factors influencing polymer degradation with rank-based machine learning.

The efficient treatment of polymer waste is a major challenge for marine sustainability. It is useful to reveal the factors that dominate the degradability of polymer materials for developing polymer materials in the future. The small number of available datasets on degradability and the diversity of their experimental means and conditions hinder large-scale analysis. In this study, we have developed a platform for evaluating the degradability of polymers that is suitable for such data, using a rank-based machine learning technique based on RankSVM. We then made a ranking model to evaluate the degradability of polymers, integrating three datasets on the degradability of polymers that are measured by different means and conditions. Analysis of this ranking model with a decision tree revealed factors that dominate the degradability of polymers.

CircTmeff1 Promotes Muscle Atrophy by Interacting with TDP-43 and Encoding A Novel TMEFF1-339aa Protein.

Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that are involved in various physiological and pathological processes, but their role in muscle atrophy remains unknown. Global circRNA expression profiling indicated that circRNAs are involved in the pathophysiological processes of muscle atrophy. circTmeff1 is identified as a potential circRNA candidate that influences muscle atrophy. It is further identified that circTmeff1 is highly expressed in multiple types of muscle atrophy in vivo and in vitro. Moreover, the overexpression of circTmeff1 triggers muscle atrophy in vitro and in vivo, while the knockdown of circTmeff1 expression rescues muscle atrophy in vitro and in vivo. In particular, the knockdown of circTmeff1 expression partially rescues muscle mass in mice during established atrophic settings. Mechanistically, circTmeff1 directly interacts with TAR DNA-binding protein 43 (TDP-43) and promotes aggregation of TDP-43 in mitochondria, which triggers the release of mitochondrial DNA (mtDNA) into cytosol and activation of the cyclic GMP-AMP synthase (cGAS)/ stimulator of interferon genes (STING) pathway. Unexpectedly, TMEFF1-339aa is identified as a novel protein encoded by circTmeff1 that mediates its pro-atrophic effects. Collectively, the inhibition of circTmeff1 represents a novel therapeutic approach for multiple types of skeletal muscle atrophy.

Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophy.

Muscle atrophy is debilitating and can be induced by several stressors. Unfortunately, there are no effective pharmacological treatment until now. MicroRNA (miR)-29b is an important target that we identified to be commonly involved in multiple types of muscle atrophy. Although sequence-specific inhibition of miR-29b has been developed, in this study, we report a novel small-molecule miR-29b inhibitor that targets miR-29b hairpin precursor (pre-miR-29b) (Targapremir-29b-066 [TGP-29b-066]) considering both its three-dimensional structure and the thermodynamics of interaction between pre-miR-29b and the small molecule. This novel small-molecule inhibitor has been demonstrated to attenuate muscle atrophy induced by angiotensin II (Ang II), dexamethasone (Dex), and tumor necrosis factor α (TNF-α) in C2C12 myotubes, as evidenced by increase in the diameter of myotube and decrease in the expression of Atrogin-1 and MuRF-1. Moreover, it can also attenuate Ang II-induced muscle atrophy in mice, as evidenced by a similar increase in the diameter of myotube, reduced Atrogin-1 and MuRF-1 expression, AKT-FOXO3A-mTOR signaling activation, and decreased apoptosis and autophagy. In summary, we experimentally identified and demonstrated a novel small-molecule inhibitor of miR-29b that could act as a potential therapeutic agent for muscle atrophy.

Organic Matter Decomposition in River Ecosystems: Microbial Interactions Influenced by Total Nitrogen and Temperature in River Water.

Microbes contribute to the organic matter decomposition (OMD) in river ecosystems. This study considers two aspects of OMD in river ecosystems which have not been examined in scientific studies previously, and these are the microbial interactions in OMD and the influence of environmental factors on microbial interactions. Cotton strip (CS), as a substitute for organic matter, was introduced to Luanhe River Basin in China. The results of CS assay, microbial sequencing, and redundancy analysis (RDA) showed that CS selectively enriched bacterial and fungal groups related to cellulose decomposition, achieving cotton strip decomposition (CSD). Bacterial phylum Proteobacteria and fungal phyla Rozellomycota and Ascomycota were the dominant groups associated with CSD. Network analysis and Mantel test results indicated that bacteria and fungi on CS cooperatively formed an interaction network to achieve the CSD. In the network, modules 2 and 4 were significantly positively associated with CSD, which were considered as the key modules in this study. The key modules were mainly composed of phyla Proteobacteria and Ascomycota, indicating that microbes in key modules were the effective decomposers of CS. Although keystone taxa were not directly associated with CSD, they may regulate the genera in key modules to achieve the CSD, since some keystone taxa were linked with the microbial genera associated with CSD in the key modules. Total nitrogen (TN) and temperature in water were the dominant environmental factors positively influenced CSD. The key modules 2 and 4 were positively influenced by water temperature and TN in water, respectively, and two keystone taxa were positively associated with TN. This profoundly revealed that water temperature and TN influenced the OMD through acting on the keystone taxa and key modules in microbial interactions. The research findings help us to understand the microbial interactions influenced by environmental factors in OMD in river ecosystems.

Delivery of engineered extracellular vesicles with miR-29b editing system for muscle atrophy therapy.

Muscle atrophy is a frequently observed complication, characterized by the loss of muscle mass and strength, which diminishes the quality of life and survival. No effective therapy except exercise is currently available. In our previous study, repressing miR-29b has been shown to reduce muscle atrophy. In our current study, we have constructed artificially engineered extracellular vesicles for the delivery of CRISPR/Cas9 to target miR-29b (EVs-Cas9-29b). EVs-Cas9-29b has shown a favorable functional effect with respect to miR-29b repression in a specific and rapid manner by gene editing. In in vitro conditions, EVs-Cas9-29b could protect against muscle atrophy induced by dexamethasone (Dex), angiotensin II (AngII), and tumor necrosis factor-alpha (TNF-α). And EVs-Cas9-29b introduced in vivo preserved muscle function in the well-established immobilization and denervation-induced muscle atrophy mice model. Our work demonstrates an engineered extracellular vesicles delivery of the miR-29b editing system, which could be potentially used for muscle atrophy therapy.

Targeting miR-30d reverses pathological cardiac hypertrophy.

BACKGROUND: Pathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed. METHODS: The expression level of miR-30d was analyzed in hypertrophy models and serum of patients with chronic heart failure by qRT-PCR. Gain and loss-of-function experiments of miR-30d were performed in vitro. miR-30d gain of function were performed in vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, and immunofluorescence were performed to examine the molecular mechanisms of miR-30d. FINDINGS: miR-30d was decreased in both murine and neonatal rat cardiomyocytes (NRCMs) models of hypertrophy. miR-30d overexpression ameliorated phenylephrine (PE) and angiotensin II (Ang II) induced hypertrophy in NRCMs, whereas the opposite phenotype was observed when miR-30d was downregulated. Consistently, the miR-30d transgenic rat was found to protect against isoproterenol (ISO)-induced pathological hypertrophy. Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation in the promotor region of miR-30d and suppress its expression during the pathological cardiac hypertrophy. miR-30d prevented pathological cardiac hypertrophy via negatively regulating its target genes MAP4K4 and GRP78 and inhibiting pro-hypertrophic nuclear factor of activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d overexpression exhibited beneficial effects in murine hypertrophic model. Notably, miR-30d was reduced in serum of patients with chronic heart failure and miR-30d overexpression could significantly ameliorate pathological hypertrophy in human embryonic stem cell-derived cardiomyocytes. INTERPRETATION: Overexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy. FUNDING: This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J Xiao), National Natural Science Foundation of China (82020108002 to J Xiao, 81900359 to J Li), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to J Xiao, 22010500200 to J Li), Shanghai Sailing Program (19YF1416400 to J Li), the "Dawn" Program of Shanghai Education Commission (19SG34 to J Xiao), the "Chen Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG45 to J Li).

Analysis of the influence paths of land use and landscape pattern on organic matter decomposition in river ecosystems: Focusing on microbial groups.

Organic matter decomposition (OMD) is one of the important river ecosystem functions. Changes in land use and landscape pattern (LULP) have a serious influence on the OMD in neighboring river ecosystems. However, there is limited information on the influence paths of LULP on organic matter decomposition in river ecosystems. In this study, cotton strip (CS) as a substitute for investigating OMD, was introduced to the delineated catchments in Luanhe River Basin in China, meanwhile combining with remote sensing interpretation, water quality analysis, microbial sequencing, and redundancy analysis (RDA) to identify the dominant LULP metrics, water quality parameters, and microbial groups controlling the OMD. Then the structural equation models (SEMs) were used to connect these dominant controlling factors to track the influence paths of LULP on OMD in river ecosystems. RDA results indicated that construction land (CON), farmland (FAR) and landscape shape index (LSI) in LULP, total nitrogen (TN), chemical oxygen demand (COD) and pH in water quality, bacterial phyla Planctomycetes and Firmicutes, as well as fungal phyla Chytridiomycota and Basidiomycota were the dominant factors controlling the OMD (quantified by tensile strength loss (TSL) and respiration (RES)). These four microbial phyla contributed significantly to OMD. SEMs further proposed three paths to explain the mechanism of LULP influencing on OMD, which were CON - TN - Firmicutes - TSL, CON - TN - Chytridiomycota - RES, and FAR - COD - Chytridiomycota - TSL. CON promoted OMD mainly through enhancing TN content in river water to increase Firmicutes and Chytridiomycota. FAR increased Chytridiomycota by decreasing COD in river water, promoting OMD. These results will deepen our understanding of the influence of LULP on river ecosystem functions and provide valuable information for policymakers and managers to carry out watershed land planning and river management in the future.

Interactions between Escherichia coli survival and manganese and iron oxides in water under freeze-thaw.

Pathogenic survivals were dramatically affected by Fe3+ and Mn2+ under freeze-thaw (FT), and the dissolutions of manganese and iron oxides (MIOs) were also accelerated under FT. But the mutual influences of pathogenic bacterial survival and MIOs under FT have not been profoundly explored yet. In this work, aqueous systems containing Escherichia coli as well as synthetic ferrihydrite (Fh) and manganese dioxide (MnO2) were experimented under simulated FT cycles to study the mutual influences of metal oxides and bacteria survival while oxide dissolutions and appearances, bacterial morphology and activities (survival number, cell surface hydrophobicity (CSH) and superoxide dismutase (SOD)) were obtained. The results showed that broken E. coli cells by ice growth were observed, but both oxides promoted E. coli survival under FT stress and prolonged bacterial survival time by 1.2-2.9 times, which were mainly attributed to the release of Fe3+ and Mn2+ caused by FT. The dissolutions of Fh and MnO2 under FT, which took place at a low level in absence of E. coli cells, were markedly enhanced with bacterial interferences by 2-8 times and higher dissolved manganese concentrations were detected than iron. This was probably because that concentrated organic matters which were released from broken cells, rejected into unfrozen liquid layer and acted as electron donors and ligands to oxide dissolution. Compared with Fh system, more significant promotion of E. coli survival under FT in MnO2 systems were found because of more SOD generations associated with high dissolved manganese concentrations and the stronger cellular protection by MnO2 aggregations. The results suggested that FT significantly influenced the interactions between metal oxides and bacterial in water, resulting to changes in pathogen activity and metal element cycling.

Caffeine Protects Skin from Oxidative Stress-Induced Senescence through the Activation of Autophagy.

Skin cells are vulnerable to oxidative stress-induced senescence, which may lead to abnormal aging or aging-related disorders. Therefore, strategies that can ameliorate oxidative stress-induced senescence are expected to protect skin from damage, holding the promise of treating skin diseases in the clinic. This study aims to investigate whether caffeine, a well-known purine alkaloid, is able to prevent skin from oxidative stress-induced senescence, and to explore the underlying molecular mechanisms. Methods: A free radical inducer 2,2'-Azobis (2-amidinopropane) dihydrochloride (AAPH) was used to induce oxidative stress and cellular senescence in both transformed skin cells and in normal human epidermal keratinocytes (NHEKs). Ultraviolet (UV) irradiation was established as the in vivo oxidative stress model in mouse skin tissues. Cellular senescence was determined by SA ß-galactosidase staining, immunofluorescence and western blotting. Activation of autophagy was confirmed by western blotting, immunofluorescence, and transmission electron microscopy. Reactive oxygen species (ROS) detection by commercial kits, gene knockdown by RNA interference (RNAi) and receptor activation/inactivation by agonist/antagonist treatment were applied in mechanistic experiments. Results: We report that AAPH induced senescence in both transformed skin cells and in NHEKs. Similarly, UV irradiation induced senescence in mouse skin tissues. Remarkably, low dose of caffeine (<10 µM) suppressed cellular senescence and skin damage induced by AAPH or UV. Mechanistically, caffeine facilitated the elimination of ROS by activating autophagy. Using a combination of RNAi and chemical treatment, we demonstrate that caffeine activates autophagy through a series of sequential events, starting from the inhibition of its primary cellular target adenosine A2a receptor (A2AR) to an increase in the protein level of Sirtuin 3 (SIRT3) and to the activation of 5' adenosine monophosphate-activated protein kinase (AMPK). Oral administration of caffeine increased the protein level of SIRT3, induced autophagy, and reduced senescence and tissue damage in UV-irradiated mouse skin. On the other hand, co-administration with autophagy inhibitors attenuated the protective effect of caffeine on UV-induced skin damage in mice. Conclusion: The results reveal that caffeine protects skin from oxidative stress-induced senescence through activating the A2AR/SIRT3/AMPK-mediated autophagy. Our study not only demonstrated the beneficial effect of caffeine using both in vitro and in vivo models, but also systematically investigated the underlying molecular mechanisms. These discoveries implicate the potential of caffeine in the protection of skin disease.

A SIRT3/AMPK/autophagy network orchestrates the protective effects of trans-resveratrol in stressed peritoneal macrophages and RAW 264.7 macrophages.

Resveratrol gains a great interest for its strong antioxidant properties, while the molecular mechanisms underlie the beneficial effects on psychosocial stress remain controversial. In this study, we demonstrated that resveratrol protected peritoneal macrophages and RAW 264.7 cells from stress-induced decrease in the total cell count, phagocytic capability, reactive oxygen species generation, monodansylcadaverine and mitochondrial membrane potential in stressed mice. Resveratrol promoted stress-induced autophagy in both models. Modulation of autophagy by rapamycin or 3-methyladenine regulated the protective effect of resveratrol, suggesting a role of autophagy in the protective mechanisms of resveratrol. The comparison studies revealed that distinct mechanisms were implicated in the protective effect of resveratrol and other antioxidants (vitamin C and edaravone). Resveratrol promoted autophagy via upregulating SIRT3 expression and phosphorylation of AMP-activated protein kinase (AMPK). Knockdown of SIRT3 resulted in decreased autophagy and abolished protective effect of resveratrol. SIRT1 was also involved in the protective mechanism of resveratrol, although its effect on autophagy was unnoticeable. Pharmacological manipulation of autophagy modulated the effects of resveratrol on SIRT3 and AMPK, revealing the engagement of a positive feedback loop. In sharp contrast, vitamin C and edaravone effectively protected macrophages from stress-induced cytotoxicity, accompanied by downregulated SIRT3 expression and AMPK phosphorylation, and decreased level of autophagy response. Taken together, we conclude that a SIRT3/AMPK/autophagy network orchestrates in the protective effect of resveratrol in macrophages.

Autophagy is involved in the effects of resveratrol on prevention of splenocyte apoptosis caused by oxidative stress in restrained mice.

SCOPE: Resveratrol, a powerful natural compound for human health, is widely reported for its immunity-related beneficial properties. However, few works have studied its effect mechanism on immunity. The present study was conducted to investigate the effects of resveratrol on splenic immunity in restraint stressed mice and the mechanism was further studied as autophagy induction. METHODS AND RESULTS: Mice were administered with resveratrol for 7 days consecutively, fixed in restraint cages for 18 h, and recovered for 12 h after the last administration. Data showed that restraint led to spleen damages, including declined spleen index, decreased CD4(+) T-cell number, increased mitochondrial oxidative damage, and apoptosis of splenocytes. Resveratrol, vitamin C (antioxidant), and rapamycin (autophagy agonist) protected spleen functions. Meanwhile, rapamycin augmented the effects of resveratrol that were abolished by chloroquine (autophagy antagonists). Further studies showed that expressions of Beclin 1 and LC3ß required in autophagy development were significantly upregulated by resveratrol but not by vitamin C. CONCLUSION: This study demonstrated that resveratrol preserved splenic immunity of restraint stressed mice. It is meaningful to find that autophagy, apart from reactive oxygen species clearance, is included as a potential mechanism via which resveratrol ameliorated the state of oxidative stress and thus protected splenocytes in mice.